1. Field of the Invention
The present invention generally concerns the field of intelligent medical diagnostic devices. The present invention particularly concerns an apparatus and method for interpretation by electronic means of the meaning of vaginal measurement data without the need for the user to take part in the data interpretation process, and for optional downloading of the data stored within the apparatus into an external display appliance or data analysis unit. The apparatus and method are particularly useful as an aid for the management of female patients with reduced fertility or infertility, and as a tool for natural or scientific family planning approach to birth control.
2. Description of the Related Prior Art
2.1 General Background and Problems with Competition Methods
The background of the invention of this application includes the more than 3 million unintended pregnancies that occur annually in the U.S., about half of which are attributable to contraceptive failure. The U.S. population of women that use some form of birth control comprises approximately 30 million to 40 million women. “There is no surer way to reduce the number of abortions in the U.S. and throughout the world than by improving the effectiveness of contraception” [S. J. Segal, in E. E. Wallach and H. A. Zacur, editors: Reproductive Medicine and Surgery, Mosby, 1995]. Worldwide, there has been a tenfold increase in the use of birth control over the last 3 decades, the numbers exemplified by the almost 400 million of contraceptive users in the developing world (in 1994), and by the more than 50% of couples in the reproductive age group that practice birth control. In this context, the use of the so-called natural family planning method is increasing for a number of reasons, including cost-effectiveness, health and religious considerations. Against the baseline statistics of a mere 10% to 20% chance of conception from an unprotected intercourse for a normal healthy couple in any given month, the high incidence and increasing trend of infertility (approximately 20% in the U.S.) is the other side of the background of this invention. Infertility treatment is crucially dependent on timing of procedures with respect to ovulation, and on individualized procedures with careful monitoring.
On the basic level of the art, the issue or problem is how to detect one or more reliable indicators of the fertility status which is infertile except for a few days at the so-called mid-cycle. The present application addresses the next level which is how to utilize such diagnostically useful information in a user-friendly and reliable manner so as to make it possible for the user to obtain directly the diagnostic decision on whether fertile (conception can occur) or not fertile (conception cannot physically occur), without obligating the user to make any decisions on how to interpret the measurement data. The apparatus according to the inventions of this application performs this data interpretation automatically. The methods used for the electronic probe data interpretation stem from a new understanding of the chronobiological meaning of the probe cyclic profile and of its individual features. This results in a method of assessing the periodic development of the egg in its protective microscopic sack (called the follicle) as a function of at least two biological pacemakers or “clocks”.
One competitor that attempts to serve the purpose of electronic interpretation of certain kinds of fertility data is the Persona electronic colorimeter for urine analysis from Unipath Ltd. of Britain. It consists of detecting, in a woman's urine, both the luteinizing hormone (LH) surge that typically marks the ovulation day, as well as a metabolite of estrogen, i.e., another hormone which anticipates by about one day the luteinizing hormone surge. Since, unlike my probe, the Persona depends on biochemical reagents and since the supply of the reagents is limited, the user needs to estimate on which day of her menstrual cycle she should start using the system. She does that based on her history of menstrual cycles as though the length and the timing of the present menstrual cycle were the same as in her previous cycles. Because of variable lengths of successive cycles in most women, this is a weak feature in the design of the Unipath system. Even more significantly, this weakness is also involved in its ovulation-predicting method, which is based on data pooled from other women and on the user's estrogen and LH data history, if available, both stored in the Persona's memory.
The Persona Contraceptive System of Unipath Ltd. is an attempt at an improvement upon the commercially available luteinizing hormone (LH) kits that only aim to detect the LH surge in the woman's urine. Two beneficial features have been introduced by Unipath Ltd.: 1. the addition of an estrogen metabolite to the diagnostic measurement so as to anticipate the LH surge, and 2. the measurement is performed instrumentally rather than as a subjective judgment of a color change by the woman-user. However, ovulation as such is not detected by the Persona device. Ovulation is, in fact, known to fail to occur in approximately 20% of the follicles that, triggered by the LH, undergo the cyclic event of follicle rupture. Ovulation also fails to occur with another type of follicles, the so-called luteinized unruptured follicles. Yet, the LH surge can be seen in either case and is therefore a false indicator.
One other problem of the Persona is that the urinary concentration of the estrogen metabolite E3G peaks only within 24 hours prior to the LH surge. This is not at all early enough to serve as a marker of the beginning of the fertile phase. The Unipath literature states that “a sustained rise in E3G can be used to identify the start of the fertile phase”, referring to a slow gradual increase that eventually becomes the peak of E3G concentration. While the Unipath Persona Personal Contraceptive System has been introduced to the market in Britain, the statistical testing for its reliability is still in progress. The attempt by Unipath to use an ill-defined rise rather than the peak in the cyclic profile of the estrogen metabolite is not a viable solution. Even if the ill-defined E3G rise in the urine were correlated with a clearly defined early stage of egg development towards ovulation, a serious flaw of the Unipath method is their reliance on pooled, rather than actual single-event, data in defining the start of the fertile period in a given cycle.
The gradual increase of the E3G concentration in the urine, proceeding at different rates in different cycles, can hardly be predictably associated with the beginning of the fertile period. Estrogen is known to have both stimulatory and inhibitory effects on LH secretion and, to be effective as a stimulant, must rise to its peak levels (>150 to 200 pg/mi) and must remain elevated for at least 36 hours [J. Hotchkiss and E. Knobil in E. Y. Adashi, J. A. Rock and Z. Rosenwaks, editors: Reproductive Endocrinology, Surgery and Technology, Lippincott-Raven Publishers, 1996]. The E3G profile does not reflect the local interplay with progesterone but only reflects clearance of one of at least 10 metabolites of estrogen from peripheral blood circulation into the urine after oxidative conversion in the liver. Whatever the rate of this clearance process, there are local mechanisms due to which the quantification of ovarian steroids in peripheral blood or in urine is rendered “interesting but of little value in predicting the genital end-organ effect” [C. J. Verco, in A. M. Siegler, editor: The Fallopian Tube. Basic Studies and Clinical Contributions, Futura Publishing Company, 1986].
Ovarian vein-to-artery exchange of steroids, prostaglandins and other bioactive substances is a local transfer mechanism. As such, it enables local regulation of ovarian, tubal and uterine functions, with genital organs therefore exposed at any given time to hormonal concentrations that are higher than the peripheral concentrations. This kind of acute exposure is of particular relevance to the regulation of the physiology of the genital organs. The local, as opposed to peripheral, blood concentrations of the steroid hormones are also believed to control the innervation of the female genital tract. The cervix, like the isthmus region of the fallopian tube, has a particularly dense innervation by, for example, the vasoactive intestinal polypeptide nerve [C. Owman et al., idem.]. These examples of local and acute regulatory mechanisms remain undetected by the prior art techniques that focus on peripheral variables. Such peripheral or systemic techniques then resort to pooled, averaged, data as though synchronization of menstrual cycles were somehow present.
The flawed assumption of similar timing of menstrual cyclic events from one cycle to another has been a problem for the microprocessor controlled thermometers. Since the late sixties, the microprocessor technology has been applied by a number of people to the well-tried basal body temperature approach to family planning. These products are not recognized as medically valid even if they may be acceptable to some of the older physicians. This is because of the fact that the so-called basal body temperature (BBT) is a systemic variable or a secondary parameter that reflects, among other things, progesterone rise in blood after ovulation, usually one or two days later. Even though in some women in some cycles a dip in the temperature graph may be observed one day before the post-ovulatory temperature rise, it is clear that the BBT method is of little value due to its lack of predictive capability and due to its fundamental unreliability.
Another electronic fertility monitor that did attempt to anticipate ovulation was the Cue fertility monitor from Zetek. It consisted of two resistivity sensors: one oral (to detect a change in resistivity of saliva in the mouth some 5 or 6 days before ovulation), and one vaginal (to detect a change in resistivity of the mucus in the vagina, marking ovulation). The Cue monitor measured the concentration of electrolytes, particularly common salt, in the saliva and in vaginal mucus. These are remote indicators of the physiological changes that are associated with the fertility status of the cervical uterine tissues. The Cue monitor was unreliable and it did not provide for a distinction between fertile versus not fertile days. It was also cumbersome to use, expensive, and not at all feminine in any sense.
The inability to predict ovulation is inherent in U.S. Pat. No. 5,209,238 (Sundhar, May 11, 1993) which purports to determine empirically the presence of a viable egg by detecting the simultaneously elevated readings of four vaginal measurements. The measured parameters are the basal body temperature (BBT), the concentration of luteinizing hormone (LH) postulated to be present on the vaginal wall surfaces, the alkalinity of cervical mucus (pH), and the viscosity of cervical mucus detected as an increased pressure (p) on a thin diaphragm. The presence of a viable egg is defined by Sundhar as all four parameters registering above respective threshold values which his patent leaves unspecified.
Sundhar states that the cervical fluid, which provides for the elevated values of pH and p, appears at the mouth of the cervix only after the rupture of the follicle. He states that the alkalinity and the density of the mucous fluid are “the determining factors of ovulation”. He does acknowledge the fact that the BBT becomes elevated only about 24-48 hours after the rupture of the follicle to which he assigns its origin. He also appears to recognize that LH levels, on the other hand, peak some 18 hours before the event which means that by the time ovulation occurs, the LH is back to low levels. Regardless of whether he therefore works with parameters that do not, in fact, change at the time of ovulation and whether or not they change simultaneously to justify his definition of the presence of a viable egg, the fact is that there is no capability to anticipate ovulation by several days with his method and apparatus. Neither does his patent define the end of the fertile period (which in his terminology would be ‘viable egg no longer present’). The Sundhar patent does neither address nor satisfy the need for the determination of the window of fertility even if it does seek a correlation between several parameters associated with the menstrual cycle. Sundhar does not include the day of cycle among his set of parameters.
In contrast, Weilgain Precision Products Ltd. of Hong Kong have a U.S. Pat. No. 5,515,344 (Ng, May 7, 1996) teaching a menstrual cycle meter that is a microprocessor-based calendar which basically provides for the day of cycle as the tracked parameter. The so-called menstrual cycle meter calculates the fertile and infertile periods of the current menstrual cycle based on at least two previous cycle lengths and the respective first days of the cycles. The apparatus purports to indicate the expected sex of a baby that is likely to be conceived on any given day during the calculated fertile period. This purpose of the Ng menstrual cycle meter may be controversial and the method is fundamentally flawed but the patent filed from Hong Kong may also be taken as evidence of public interest in fetal sex pre-selection in the context of small family planning.
In the U.S., this topic is often associated with Dr. L. Shettles, the author of the book “How to Choose the Sex of Your Baby” [Doubleday, 1981]. According to “Dr. Shettles Method”, the critical variable for fetal sex preselection is the timing of intercourse with respect to ovulation. Briefly, and without necessarily subscribing to it, I would note that the method teaches that, to aim for a boy, intercourse should be timed to occur on the day of ovulation or the day after; the more difficult to pre-select female gender is to be aimed at by timing intercourse “several days before ovulation but preferably not closer than two days before”. It will be clear from the description below that the intelligent probe of the present invention is eminently suited to be a timing tool in such a process.
The menstrual cycle meter of Ng is related to the Shettles Method. The problem with the Ng invention is that it relies on the old, failed, calendar or rhythm method of birth control. The method had failed in terms of its high contraceptive failure rate resulting from its assumption of similar timing of menstrual cyclic events from one cycle to another, one of the fundamental flaws discussed above in connection with the other prior art.
The erroneous assumption that women usually have 28-day cycles and that they ovulate on day 14 may cause problems even outside of the arena of fetal sex-preselection. Problems can occur in standard monitoring of pregnancy, if relying on the method or the date of the so called pregnancy wheel. Indeed, miscalculations of the expected date of delivery, in the absence of diagnostic means such as ultrasound, have even led to the induced labor of many premature babies. It will be clear, from the description that follows, that the present invention has useful applicability also in pregnancy planning.
Weinmann's U.S. Pat. No. 5,240,010 (Weinmann, Aug. 31, 1993), filed from Israel, is another piece of evidence that electronic interpretation of multiple input data related to fertility does not necessarily lead to a meaningful acceptable solution of the problem posed by the need to anticipate fertility status changes, including the need to predict ovulation. Merely processing a multitude of inadequate data inputs, in the hope that synergistically they may achieve adequate fertility prediction, does not do the job even if one of the inputs is some vaginal impedance parameter. Weinmann's other inputs are vaginal temperature in lieu of the BBT for the end of the fertile period, and a rhythm method calculation for the beginning of the fertile period.
2.2 The Need to Monitor Folliculogenesis
Monitoring of ovarian function is absent in competitors' prior art. What is missing in the cited prior art is a specific link between the employed indicators and the events that occur well before ovulation, that is the link with specific early stages of ovarian function. Ovarian function in every menstrual cycle involves the formation and maturation of the dominant follicle in the ovary, followed by the follicle rupture and the release of the egg (ovulation). Moreover, the prior art of the competitors does not work with the various biological pacemakers (such as in particular the circamensual and the circhoral “clocks”) that are inherently involved in my present patent application. To be sure other pacemakers exist in the reproductive system, including, significantly, one in the oviducts or fallopian tubes [S. Anand, in A. M. Siegler, editor: The Fallopian Tube, Futura Publishing Company, 1986], and they are all likely to be involved in the dominant follicle's prerogative to synchronize them (vide infra, this section).
Ovarian function and its significance for the invention cannot be understood without consideration of the fact that there are other endocrine organs that communicate stimulatory or inhibitory signals to the ovary and to which the ovary feeds back its signals. Since in this manner there is a connection between the hypothalamus and the pituitary gland of the brain and the two ovaries, this connection is called the hypothalamic-pituitary-ovarian axis.
The mediators of communication among the organs are certain hormones released into the blood circulation. As indicated in section 2.1, it is some of these mediator compounds that the competitors' prior art targets, directly or even indirectly, as the handle on the timing of the menstrual cycle. Briefly, the peptide follicle-stimulating hormone (FSH), released by the pituitary, primarily functions to induce proliferation of the follicular granulosa cells in one of the two ovaries and to stimulate an aromatase enzyme (which is an electron transfer enzyme) for estrogen synthesis. The other pituitary peptide, luteinizing hormone (LH), then stimulates the transformation of estrogen-secreting stromal cells in the selected ovary into progesterone-secreting cells, and promotes ovulation. The predominant ovarian hormones, that exert peripheral, central and intraovarian effects, are the sex steroids estrogen or estradiol (E2) and progesterone (P4); there are also other steroids at play in the ovarian and hypothalamic-pituitary events. In addition, there are other peptidic reproductive hormones known as nonsteroidal ovarian factors (e.g. inhibin, oocyte maturation inhibitor, gonadotropin surge-inhibiting factor and certain growth factors).
The properly orchestrated actions of all these substances are known to be necessary for the functioning of the menstrual cycle. The endometrium and the cervix uteri are very sensitive detectors of the hormonal signals and of their orchestration (i.e., of their relative timing with respect to each other) [B. M. Sanborn et al., J. St. Biochem. 9:951, 1978; G. I. Gorodeski et al., J. din. Endocrinol. Metab. 70:1624, 1990; G. Fried et al., Human Reprod. 5:870, 1990; G. I. Gordeski et al., Fertil. Steril. 47:108, 1987]. The periodically recurring development of ovarian follicles, in preparation for the periodically recurring ovulation, is called folliculogenesis. The process of folliculogenesis is the essence of ovarian function from the perspective of ovulation-prediction and it involves four basic conditions in which the many follicles, present in the two ovaries, can be found: resting, growing, atretic, or ready to ovulate [A. L. Goodman and G. D. Hodgen, in R. O. Greep, editor: Recent progress in hormone research, Academic Press, 1983]. Most of the follicles remain resting but, at the beginning of every menstrual cycle, a group or cohort of follicles are recruited to grow; only one of these will mature and will normally ovulate, with the rest of the group succumbing to atresia (death).
It is well established that women and other primate females produce a single fertilizable egg approximately every four weeks. The actual duration of this circamensual (or approximately one-month) period is not a constant; rather, it ranges from about three weeks to about five weeks wherein lies the need for and the challenge of reliable monitoring of the menstrual cycle and of reliable anticipation of the brief fertility window. The brevity of the fertile phase (about 5 days) is due to the limited viability or life-time of the ovulated egg (i.e., the egg released from the successfully matured dominant follicle) coupled with the pre-ovulation fertile days that are due to the life-time of the sperm which survive longer than the ovulated egg but only in the now-hospitable environment of the cervical mucus and epithelium at around the time of ovulation. Allowing for the longer longevity of the sperm is the most difficult challenge for scientific family planning.
Folliculogenesis is a continuous process with well-defined morphologic and endocrine dynamics or timing of events. The dynamics of this process have been characterized biologically and separated into the intervals or stages of recruitment, selection, dominance and ovulation [G. D. Hodgen, Fertility and Sterility 38:28 1,1983]:
TIMING OF THE FOUR STAGES OF FOLLICULOGENESISSTAGES IN AN IDEALIZED,STEREOTYPICALMENSTRUAL CYCLERECRUITMENTSELECTIONDOMINANCEOVULATIONApproximate cycle days1 to 5 ± 16 ± 18 to 1214 ± 1
The interval of recruitment begins at the end of the previous cycle, from the onset of menstrual bleeding to approximately day 5 7 of the current cycle. During this interval, LH induces an “angiogenesis” factor from the theca cells, increasing the blood supply and estrogen synthesis by the recruited follicles.
The term “selection” indicates the reduction of the recruited group of follicles down to the species-characteristic ovulatory quota which in women and related primates is one. Selection is the culmination of recruitment on day 6±1. Typically only one of the two ovaries sponsors recruitment and selection of the single dominant follicle which is destined for ovulation. (Spontaneous multiple ovulation is atypical, although not a rarity. It is expected that multiple ovulation should be recognizable with the probe of this invention.)
Dominance is the interval of follicular growth that precedes ovulation after selection and is achieved typically between days 8 and 12 of the stereotypical menstrual cycle. It appears that the one follicle that most rapidly acquires aromatase activity and LH receptors probably is the one that becomes dominant, overcoming an ovarian inhibitory activity that suppresses the less-developed follicles of the recruited group, in the midfollicular phase. The increasing quantities of estrogen are secreted by the dominant follicle and play a critical role in coordinating the development of the different parts of the reproductive tract: estrogen priming is essential in the brain as well as in the cervical epithelium and mucus (where the probe detects its effect) and in the oviduct. The dominant follicle has a straightforward prerogative: it must synchronize the entire reproductive system for ovulation, fertilization and implantation. Failing that, conception will not be possible (such as in the case of the luteal phase defect). This is the essence of the “pelvic clock” or “zeitgeber”, the ovarian circamensual pacemaker. However, the mechanism is made more complex by the participation of other pacemakers, including at least one in the brain, in the reproductive cycle (vide infra).
Once the dominant follicle has achieved the necessary size and adequate systemic hormonal effects, final maturational changes within the follicle stimulate ovulation. Endocrinologically, the most prominent marker of impending ovulation is the LH surge which anticipates ovulation within 9 to 12 hours and which is under the control of the ovarian pacemaker that dictates the timing of these events. At the time of the LH surge, the granulosa cells surrounding the follicle become transformed or “luteinized”. They become specialized toward synthesis and secretion of progesterone and this rapid increase in progesterone levels is responsible for inducing and coordinating several physiological changes in the reproductive system; the ovulation marker dip or minimum of my prior art fertility probe detects one of them, due to the sensitivity of the epithelium and mucus in the posterior fornix region to the sex steroids.
2.3 The Kirsner Prior Art and the Present Invention
The present invention provides an improvement applicable to any other monitor of the folliculogenesis process that has a similar capability to provide a cyclic profile with this high information content in one variable. Based on the repeatability of the characteristic profile features from cycle to cycle, the data makes it possible to interpret the probe cyclic profile so as to recognize the various phases of folliculogenesis and, in so doing, to distinguish the brief fertility window from infertility and thus anticipate ovulation in a rational manner.
FIG. 10 depicts the features of a menstrual cyclic profile that was yielded by a woman answering the idealized, stereotypical or baseline characteristics. The length of the cycle and its apparent dynamics (or timing of the various intervals or stages involved in folliculogenesis) are chosen to correspond to the stereotypical case of 28 day-long menstrual cycle. The first minimum, FM, occurs in this cycle on day 6 and reflects the selection stage that is the culmination of recruitment. We are justified to view the depicted data on day 6 as FM even m the absence in this particular profile of the prior data points that were not obtained on account of hygienic considerations during the previous days of menstrual bleeding; many other cyclic profiles have consistently shown this first minimum, as illustrated in FIGS. 11 and 12.
FIG. 10 further depicts the wide and high first peak FP that describes the interval of dominance. This is then followed by the window of fertility WF which is defined by boundaries BF (begin fertility) and EF (end fertility) with three labeled features flanked by the boundary points, all within the window WF. These five days define the fertile period during which conception is possible due to the life-times of both the egg and the sperm with the proviso stated below in the discussion of the data interpretation program in relation to the need for large-scale statistical data confirming this definition of WF.
We know from empirical evidence that the third minimum, labeled OM, marks the day of ovulation because in separate experiments it coincided with the day of the LH surge detected in the subject's urine by standard laboratory procedure, radio-immunoassay. (OM also always preceded the rise in BBT when monitored for comparison.) It will be clear to those skilled in the art that ultrasonic evidence of follicle collapse is a more reliable proof of ovulation, if backed by other data eliminating the possibility of follicle collapse without egg release; however, ensuing pregnancy is the only definitive proof of ovulation in absolute terms. Such proof will be obtained in a planned clinical trial, discussed below. The temporal relationship (one day) between the ovulation marker OM and the second peak SP is consistent with a steroid signal from the selected ovary signaling its readiness to release the egg from the dominant follicle.
The most important feature to point out about FIG. 10 is that, while the two horizontal thresholds FT and OT are constants dependent on the calibration of the probe electronics, the boundary days of the fertility window WF (BF and EF, here days 12 and 16) are variables that change from cycle to cycle. This is documented in Table 1 (Window of fertility boundary days for six menstrual cycles). Table 1 shows cycles with cycle lengths ranging from 24 to 30 days, with the beginning of fertility BF ranging from day 9 to day 13, and end of fertility EF ranging from day 13 to day 17. The Table demonstrates how seriously wrong the assumption of the same timing of events in different cycles would be if the assumption were used for the data interpretation method, as has been the case in the prior art by certain competitors. The Table shows that two cycles of a given cycle length (here 26 days) can have two different beginnings of the fertile window (here day 9 and day 13, respectively). The Table also shows that a given beginning of the fertile window (here day 13) can occur in cycles of different lengths (here cycle lengths from 24 to 30 days).
I now introduce a new discovery that is most important for the construction of the data-interpretation program described and claimed below. Due to the mandatory synchronization of the various pacemakers involved in the natural cycling process of the reproductive system, there appears in the probe cyclic profile a phenomenon that I describe more fully below under the name of “synchronization arrest”. In connection with it, I have now discovered that the beginning of fertility, BF, is predicted by the amplitude of the probe signal on the day of the first minimum, FM; this is also depicted in FIG. 10.
TABLE 1WINDOW OF FERTILITY BOUNDARY DAYSFOR SIX MENSTRUAL CYCLESBFEFOMBeginningEnd ofOvulationLength ofCycleof FertileFertileLength ofMarkerLutealNumberWindowWindowthe CycleDayPhaseA. BASELINE CYCLESPM11216281513PM21317301614PM3 913261214Baseline9-1313-1726-3012-1613-14RangeB. NON-BASELINE CYCLESLK4*13182617 9LK513172416 8LK61317281612Non-baseline1317-1824-2815-16 8-12RangeOverall9-1313-1824-3012-16 8-14Range*Cycle LK4 is a short cycle, as are cycles PM3 and LK5 (<28 days). However, unlike cycle PM3, cycles LK4 and LK5 are abnormal cycles with short luteal phases (<11 days). Both have abnormally long follicular phases, being short cycles, unlike the baseline cycle PM3 which is short simply because of its short follicular phase (with the normal luteal phase of 14 days). Cycle LK4 is unusual in that there are three, ratherthan just one, decreasingreadings after A the second peak. Cycle LK4, which was recorded by a woman with a history of amenorrhea and of ovarian cysts before her two pregnancies, is considered to be a case of asynchrony between follicle maturation and the pituitary signal to ovulation [A. J. Zeleznik, in E. Y. Adashi and P. K. C Leung, editors: The Ovary, Raven, 1993, pp.41-45; G. F. Erickson in J. Schoemaker andR. Schats, editors: Ovarian Endocrinopathies, Parthenon, 1994, pp. 103-115; E. L. Nestour et at, J. Chin. Endocrinol. Metab. 77: 439, 1993], involving the circhoral clock of the hypothalamic GnRH pulse generator on which the circamensual ovarian clock is “obligatorily dependent’ IJ. Hotchkiss and Knobil in E. Y. Adashi, J. A. Rock and Z. Rosenwaks, editors: Reproductive Endocrinology,Surgeiy, and Technology, Lippincott-Raven Publishers, 1996].
The multitude of repeatable measurable features of the probe cyclic pattern makes it possible to determine the boundaries of the fertile window for every individual cycle rather than having to rely on some assumption of unchanged timing of these events from cycle to cycle in the manner of the methods of prior art discussed above. The Kirsner method of electrometric monitoring of the tissues and secretions in the posterior fornix region for the end-organ effects of the endogeneous bioactive substances is a significant improvement upon the use of the hormone concentrations by the prior art competitors such as Unipath Ltd. Reliance on the hormone concentrations to define the fertile period is an inherently unreliable approach because the hormones are merely the input signals into the physiological mechanism of fertility status rather than indicators of the fertility status per se.
Monitoring of the end-organ effects may produce two kinds of deviations from the idealized, stereotypical menstrual cycle. These deviations from stereotype are variously considered to be consequences of the industrial and post-industrial age lifestyle, diet and environmental estrogens or, more generally, pollution. Chemically-speaking, free radicals and abnormal cross-linking of macromolecules in the tissues are often involved. These are electron transfer reactions whose effects are detectable by the Kirsner probe but not by the other prior art techniques including the Unipath Persona. Those techniques cannot therefore detect the deviations from “norm”, or stereotype, which is one reason why the concept of the stereotypical menstrual cycle continues to be perpetuated in the literature. The deviations of the first kind are the merely quantitative variations of the idealized menstrual cycle, leading to near-stereotypical cyclic profiles such as those included in FIGS. 11 and 12. The other kind of deviation is more serious, causing qualitative changes diverging from the stereotype, leading to aberrant cyclic profiles associated with reduced fertility and female infertility; this includes, for example, the case of the quite frequently occurring luteal phase defect (FIG. 22). Even some of the near-stereotypical profiles may turn out to reflect more than biological variables, and may be found to represent a syndrome (e.g., the short luteal phase cycles LK4 and LK5, particularly cycle LK4). Adjustments to the programming of the intelligent probe may result from the forthcoming clinical trials. Any such adjustments will be within the scope of this invention.